Intelligently controlled spectrometer methods and apparatus

ABSTRACT

The present invention relates to improving the ability of a hyphenated instrument to analyze a sample benefiting from having the first instrument&#39;s analysis of the same sample. A fast switching mechanism can be used as the interface between an ion mobility spectrometer (IMS) and a mass spectrometer (MS) such that the obtained IMS spectrum is converted into a timing diagram that controls the vacuum inlet&#39;s size dynamically during analysis of a neutral and/or charged chemical and/or biological species such that a smaller pumping system can be used.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/703,868, filed on May 4, 2015, which is a continuation ofU.S. patent application Ser. No. 12/764,808, filed on Apr. 21, 2010,which is a continuation in part of U.S. patent application Ser. No.11/776,392, filed on Jul. 11, 2007, and claims the benefit of andpriority to corresponding U.S. Provisional Patent Application No.61/171,447, filed Apr. 21, 2009 respectively; the entire content ofthese cross-referenced applications is herein incorporated by reference.

BACKGROUND OF THE INVENTION

Most analytical instruments have been developed to be used as individualunits for analysis of a sample. Some of these individual units have beencombined to give more information from a single sample run. Thesecombined individual units still work as separate analysis tools in thata full run or spectrum is taken for each unit, but the first unit cantransfer separated components of the sample to the next unit.Effectively using multiple analytical instruments as a hyphenatedinstrument allows analysis of a sample based on multiple analyticalprinciples with limited sample usage and instrument run time.

The present invention relates to improving the ability of a hyphenatedinstrument to analyze a sample benefiting from having the firstinstrument's analysis of the same sample. For example, a fast switchingmechanism can be used as the interface between an ion mobilityspectrometer (IMS) and a mass spectrometer (MS) such that the IMSspectrum obtained outside the vacuum chamber is converted into a timingdiagram that controls the vacuum inlet's size dynamically duringanalysis of a neutral and/or charged chemical and/or biological speciesso that a smaller pumping system can be used.

SUMMARY OF THE INVENTION

A device and/or program that may be used to control a vacuum inlet'ssize dynamically during analysis of a neutral and/or charged chemicaland/or biological species. With a dynamically controlled vacuum inlet,only a smaller amount of gas would be needed to be pumped for theanalysis to be conducted in the vacuum chamber; an ion mobilityspectrometer-mass spectrometer (IMS-MS) instrument can be constructed ina compact form when using a dynamically controlling the vacuum inlet. Asa non-limiting example, a portable ion mobility spectrometer-massspectrometer (IMS-MS) instrument can be constructed in a compact formwhen using a dynamically controlled vacuum inlet for the MS.

The simplified example of this device is shown below in Scheme 1. Invarious embodiments, a signal detector outside the vacuum chamber can beused to detect the arrival of the sample of interest, and then use thedetected signal to generate programs to control the vacuum inlet. In oneembodiment, the program(s) is used to control the timing for opening andclosing valves at the vacuum inlet. Scheme 2 below shows a non-limitingexample where the open valve timing is controlled using the arrival peaktiming in an IMS spectrum.

Not only the signal from an IMS, the valve timing can be controlled byrunning other analytical and preparative separation methods (in the gasor liquid phase) for given sample(s) prior to the analysis in the vacuumsystem, such as mass analysis. Many known instrumental methods can beused to obtain sample arrival information and control the vacuum valvetiming for mass analysis, such instruments may include, but not limitedto, IMS with Faraday plate detector, gas chromatography (GC) with a FIDdetector, liquid chromatograph (LC) and/or electrophoresis with a UVdetector, and a variety of separation and/or detection methods and theircombination that could used before entering the vacuum chamber.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other aspects, embodiments, and features of theinventions can be more fully understood from the following descriptionin conjunction with the accompanying drawings. In the drawings likereference characters generally refer to like features and structuralelements throughout the various figures. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the inventions.

FIG. 1 shows a fast switching valve as the interface between an IMS anda MS.

FIG. 2 shows an IMS spectrum obtained outside the vacuum chamber beingconverted into a timing diagram.

FIG. 3 shows the timing of a switching valve for an IMS spectrum inmilliseconds.

FIG. 4 shows valve timings for targeted explosive chemicals in an IMSspectrum.

FIG. 5 shows valve opening timing for the ion mobility spectrum of TNTand RDX.

FIG. 6 shows an aperture constructed of a piezoelectric material.

FIG. 7 shows 2 and 4 segmented metalized electrodes.

FIG. 8 shows the directions that the aperture may increase.

FIG. 9 shows an alternative embodiment of the vacuum inlet that can becontrolled by a mechanical arm.

FIG. 10A-B shows a configuration of a portable IMS-MS system; 10A is thefront view and 10B is the top view.

FIG. 11 shows the parts used to measure the mobility outside the vacuumchamber.

FIG. 12 shows a pulsed inlet using a deformed elastomer.

FIG. 13 shows a pulsed inlet using a torsion seal.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

The piezoelectric (or other suitable material) valve/interface can beused to control the amount of ions entering a mass spectrometer. Thevalve/interface open/close timing can be controlled such that thevalve/interface is open only when ions are passing through thevalve/interface instead of being constantly open. The open valve timingcan be controlled by running a spectrum of the sample prior to massanalysis, such as an IMS spectrum, but not limited to this instrument.Any known instrument can be used to control the open valve timing formass analysis, such as: GC, IMS, LC, CE, etc, but not limited to onlythese. Current mass spectrometer systems have the valve/interfaceconstantly open. This invention reduces the vacuum pumping requirementfor the mass spectrometer. For example, if the vacuum system is open tothe atmospheric pressure for 20% of the time, then the vacuum pump mayonly need to handle ⅕ of the load, therefore the pumping system can bemuch smaller. This method is particularly meaningful for portable massspectrometer applications.

The term ion mobility separator, and ion mobility spectrometer, and ionmobility based spectrometers are used interchangeably in this invention,often referred to as IMS, including time-of-flight (TOF) IMS,differential mobility spectrometers (DMS), field asymmetric ion mobilityspectrometers (FAIMS) and their derived forms. A time of flight ionmobility spectrometer and their derived forms refers to, in its broadestsense, any ion mobility based separation device that characterize ionsbased on their time of flight over a defined distance. A FAIMS, a DMS,and their derived forms separate ions based on their ion mobilitycharacteristics under high values of normalized electric field. The IMSsystems may operate in different drift media, such as gas and/or liquid,in their pure or mixture forms. The operating pressure may vary from lowvacuum to a plurality of atmospheric pressures.

The systems and methods of the present inventions may make use of “drifttubes.” The term “drift tube” is used herein in accordance with theaccepted meaning of that term in the field of ion mobility spectrometry.A drift tube is a structure containing a neutral gas through which ionsare moved under the influence of an electrical field. It is to beunderstood that a “drift tube” does not need to be in the form of a tubeor cylinder. As understood in the art, a “drift tube” is not limited tothe circular or elliptical cross-sections found in a cylinder, but canhave any cross-sectional shape including, but not limited to, square,rectangular, circular, elliptical, semi-circular, triangular, etc. Inmany cases, a drift tube is also referred to the ion transportationand/or ion filter section of a FAIMS or DMS device.

Neutral gas is often referred to as a carrier gas, drift gas, buffergas, etc. and these terms are considered interchangeable herein. The gasis at a pressure such that the mean free path of the ion, or ions, ofinterest is less than the dimensions of the drift tube. That is the gaspressure is chosen for viscous flow. Under conditions of viscous flow ofa gas in a channel, conditions are such that the mean free path is verysmall compared with the transverse dimensions of the channel. At thesepressures the flow characteristics are determined mainly by collisionsbetween the gas molecules, i.e. the viscosity of the gas. The flow maybe laminar or turbulent. It is preferred that the pressure in the drifttube is high enough that ions will travel a negligible distance,relative to the longitudinal length of the drift tube, therefore asteady-state ion mobility is achieved. An IMS can be used at differentpressure conditions.

The present invention describes generating a timing program using afirst method; using the timing program to intelligently control theopen-close action of a vacuum inlet; analyzing a sample using a secondmethod under vacuum conditions. The present invention also describes theapparatus being designed to realize these novel methods. The inventionallows conducting analysis of the sample of interest under vacuumconditions with a reduced pumping capacity. Enabling construction of acompact/portable analytical instrument that requires vacuum operatingconditions, such as a mass spectrometer; furthermore, a portable IMS-MSinstrument is desirable.

Timing can be generated based on a theoretical calculation of knownsamples, for example, the explosives of interest have certain ionmobility, Ko, therefore the drift time of these samples in a IMS underthe given conditions are known. The vacuum inlet can be programmed toopen when these peaks arrive after the IMS analysis.

In various embodiments of the above mentioned method and apparatus, aknown instrument and/or program can be used to open and close the vacuuminlet according to a predetermined timing program. One embodiment is touse a survey scan and/or pre-run to determine the arrival time of thesample for the analysis under vacuum conditions. For example, an IMSspectrum can be obtained prior to the analysis under vacuum conditions,generating the timing program based on the drift times of the analytesin IMS spectrum, which only open the vacuum inlet when the analytesarrive at the inlet. Similarly, the timing program can be generatedusing other instruments such as: GC, LC, CE, etc, but not limited toonly these, to control the inlet to a vacuum. In alternativeembodiments, the timing program used to control the vacuum inlet couldbe predetermined based on prior knowledge of an instrument. For example,if the retention time for Protein A and Protein B are known to be 4 and6 minutes, respectively, under giving chromatographic conditions, andthen the timing program is set to open at the 4^(th) and 6^(th) minutewith a width of for instance 30 second, depending on the resolution ofthe chromatographic system.

Not only controlling the vacuum inlet, the timing program can also beused to set the operational parameters for the mass spectrometer. Forexample, when a quadrupole mass spectrometer is used, a table of m/zvalues and/or ranges that are predicted according to the ion mobilityand/or chromatographic data obtained using the first method could bepreload to the mass spectrometer. Rapid and/or selective massmeasurement using a quadrupole mass spectrometer could be achieved. Forexample, when an orthogonal TOF mass spectrometer is used, preferredorthogonal extraction timing could be selected to maximize thesensitivity of compounds to be measured using the TOF mass spectrometer.In one embodiment, an ion mobility measurement is used as the firstmethod to generate the timing program and then setting the optimal massspectrometer operational parameters according to ion mobility peakidentified on IMS; note that the IMS device could be operated eitherambient or low/high pressure conditions. The timing program used tocontrol a mass spectrometer could be generated either on-the-fly orprevious to mass measurement offline.

A preferred embodiment for this invention is to control the vacuum inletopen-close timing “on-the-fly”. The dynamic control is realized by usinga first instrument to detect arrival of the sample, opening the vacuuminlet while the sample arrives at the inlet, closing the inlet afterallowing some of the sample into the inlet; the opening and closingprocess may repeat during the course of operating the system in order toallow all sample of interest enters the vacuum with the reduced sizevacuum system. For example, using a LC with a UV detector hyphenatedwith a MS, during the LC-MS operation, the UV detector can first detectthe arrival of Protein A at the end of the LC column, and then send acontrol signal to the intelligent vacuum inlet control module to openthe inlet for Protein A, as Protein A will take ‘X’ amount of time to betransported from the UV detector to the vacuum inlet via pumping themobile phase; the vacuum inlet will open after ‘X’ delay.

In one embodiment of the on-the-fly control for the vacuum inlet (or themass spectrometer operational parameters), the ion detector of the IMSthat is in front of the mass spectrometer can be positioned at alocation that is away from the vacuum inlet. At the ion detector atleast some of the ions are detected and the rest of the ionscontinuously traveling toward the vacuum inlet of the mass spectrometer.The position of the detector may be selected to give sufficient time forprogramming the vacuum inlet or the mass spectrometer. For example, ifthe ion detector locates at 2 cm from the vacuum inlet, under anelectric field condition of 300 V/cm, for ions with mobility of 2.5cm²/Vs, it will take 2.7 ms for these ions to reach the vacuum inlet andthis amount of time can be used to program the vacuum inlet or the massspectrometer. Consideration will be given to maintain the resolution ofthe mobility separated ions while transporting the ions (using electricfield, air flow, and/or other means) from the IMS detector to the massspectrometer. The IMS detector can be any means to detect a portion ofthe ions. A common IMS detector can be a Faraday plate. The detector canbe made in a shape of ring, bar, or any other geometries where the ionbeam aiming at the vacuum inlet is not interfered.

In a variety of the IMS-MS embodiments, a quadrupole mass spectrometercould be implemented by linking the mass scan functions with the timingprogram of the ion mobility based separation. A non-limiting example isto track the DC and RF voltages that are used for the mass scan with thetiming program according to the mass-mobility correlation. In this case,once a peak is detected on the ion mobility detector in front of themass analyzer (either outside or inside the vacuum chamber), the DC andRF voltage (that determines the m/z of the ions that can pass throughthe analyzer) will not need to change over a large range of voltagechanges (especially for the RF voltage), thus it minimizes the settlingtime required for setting the mass analyzer to identify targetedcompounds. In this operation, the mass analyzer may “park” on one ormore m/z value for a short period for mass measurement, and then resumetracking the timing program. Tracking the mass analyzer setting with thetime program generated by the IMS will also prepare the MS to be readyto scan a mass range correlated from the timing program.

In addition, the load of a vacuum system needs to be controlled in amanner where the desired vacuum conditions can be maintained. Eventhough it is ideal to control the vacuum inlet completely according toarrival time of the sample, additional approaches need to be consideredwhen the inlet opening time is significant (it will overload a givenvacuum system). These approaches may include, but are not limited to:(1) modulate the vacuum inlet: open and close the inlet at a firstfrequency while no sample arrives; and then open and close the inlet ata second frequency while sample arrives; in general, the secondfrequency is substantially higher than the first frequency. Thefrequency may be, but not limited, greater then zero to MHz,particularly in tens of KHz, KHz, hundreds of Hz, tens of Hz. (2) onlyopen the vacuum inlet while significant amount of sample arrives, forexample, a threshold value could be set in the said first method, signalgreater than the threshold will be use to generate the open timing. (3)limit the number of sample to be analyzed under the vacuum conditions.

In one embodiment, a piezoelectric vacuum inlet can be used to controlamount of gas and/or sample to be introduced in to the vacuum. Asimplified non-limiting example of this instrument is shown in FIG. 1,where a piezoelectric valve 101 is used between an IMS instrument 103and a MS instrument 105. With the IMS-MS system shown in FIG. 1, acontrol and data acquisition module located on a computer; Signalscommunicated to the ion mobility separator 103 control the first gate104 and second gate 106 of the ion mobility separator, at least aportion of the ions are allowed to enter the ion mobility separator andthen allowed to pass through the second gate 106. Drift time (ormobility) of ions are first measured at the ion detector/collector 107.FIG. 1 shows an aperture 111 constructed of a piezoelectric material112.

The device to restrict the a gas/sample flow does not need to be apiezoelectric valve, any means to control a vacuum inlet sizedynamically during analysis of a charged species would be considereduseful, such as; magnetic actuator, piezoelectric actuator, mechanicalactuator, but not limited to these.

The system could be operated as: (1) IMS survey scan, acquiring singleor more spectra; (2) Identifying a peak of interest by the peak's:location, drift time, width, and height to generate a timing diagram forcontrolling the size of the vacuum inlet. A non-limiting example isshown in FIG. 2. In this example, the open valve timing 202 is the sameamount as the peak timing in the IMS spectrum 205 generated by from adetector outside the vacuum inlet.

An IMS spectrum 305 is taken has a total spectrum length of 20 ms. Thedetected peak locations are: 8, 10, 12 ms, with a peak width of 0.2 ms.A timing program (diagram) 302 can be processed to look like FIG. 3,such that the vacuum inlet can be opened at 8, 10, 12 ms for a windowwidth at least 0.2 ms. In this non-limiting case, the vacuum inlet onlyneeds to be open (0.2×3/20=0.03) 3% of the time. Therefore, in averageonly 3% of the pumping load is required for this non-limiting example.

A non-limiting specific example of targeted chemicals to be detected isshown in FIG. 4. Drift times in milliseconds for the targeted chemicalsare: NG=5.5, TNT=6, RDX=6.5, PETN=8.5, and HMX=9.5 in the IMS spectrum405. The vacuum inlet will open at the indicated shaded timing areas inthe timing diagram 402. The opening timing is not based on the surveyscan and is therefore controlled dynamically. The opening timing ispreset according to the instrument application purpose. For CWAdetection, the opening timing can be completely different from thisnon-limiting specific example.

Another non-limiting example is under a situation where rapid open andclosing of the inlet is required. Under this situation, many ionmobility peaks need to be sampled in a vacuum, the piezoelectric valvemay not be able opened/closed fast enough depending on how close are theadjacent peaks (arrival time) of the sample components in a ion mobilitybased separation. In this case a wider window may be used to coverseveral peaks, i.e. open vacuum for a longer period of time. Theduration of the open/closed valve is based on IMS data obtained outsidethe vacuum chamber. An example of this situation is shown in FIG. 4 forthe TNT and RDX peaks, where the timing program 402 has a wider openingwidow for both peaks to enter the inlet. It is worth noting: when thetiming program is used to adjust the operational parameters for a massspectrometer, the mass spectrometer can be guided either to “park” atthe m/z for TNT and then “park” at the m/z for RDX, or scan a m/z rangethat covers the TNT and RDX ions.

In a variety of embodiments, the above example illustrated the basicoperation of a mobility indexed mass analysis (MIMA) method for theIMS-MS system. The MIMA operation method includes, but not limited to,using measured ion mobility of a sample to control the mass spectrometeroperation for the combined ion mobility—mass analysis involving,introducing mobility separated sample components to a mass spectrometer,adjusting necessary parameters of mass spectrometer systems andsubsystems (e.g. ion guides for focusing or storage, lens, analyzer,detector) to the optimized conditions for the analysis of targetedsample components, analyzing m/z of targeted sample components. The m/zof targeted sample components can be predicted based the mass-mobilitycorrelations. Depending on the IMS-MS system configuration and purpose,analyzing ion masses (m/z) may include, but is not limited to, (1)setting the mass spectrometer to analyze one or more m/z to confirm theion mobility measurement. The method is generally used in detection oftargeted compounds (such as in explosive detection) using a scanningtype of mass spectrometer, such as quadrupole, ion trap, triplequadrupole, quadruple—time of flight MS, ion trap—time of flight MS,etc. If the ion mobility spectrometer has already detected a targetcompound, e.g. nitroglycerine (NG) in a sample (FIG. 4), the massspectrometer will be adjusted to analyze the m/z that related to the NGin order to confirm the IMS detection. In another example, if themeasured ion mobility corresponds to more than one m/z values of thecompounds of interest (based on the database of the compounds ofinterest), then the MIMA method will guide the mass spectrometer toanalyze more than one m/z of the ion mobility separated sample peak. (2)setting the mass spectrometer to scan over a mass range that isdetermined using measured ion mobility based on the mass-mobilitycorrelation. This method is used for general purpose IMS-MS analysiswithout considering a list of targeted compounds; it could limit themass range needed to be scanned and potentially improve IMS-MS systemduty cycle. In general, in a given drift media, measured ion mobility(especially under low field conditions) is directly correlated to theion mass (m/z), the variation in the mass-mobility correction is relatedto the structure of the ions. By knowing the possible masses andstructures corresponding to an ion mobility value (via either empiricalmeasurements or theoretical calculations), the mass range that needs tobe scanned for an ion mobility value can be determined based on thisknown relationship. Besides the mass range described above, the MIMAmethod can also be used to control other parameters on the massspectrometer, these parameter may include, but are not limited to, massscan rate, mass resolution, mass calibration, DC and/or RF voltages onthe analyzer, ion energy, etc.

In one embodiment, with a given pumping power, the amount of time forthe inlet to open can be limited. A approach can be taken by opening andclosing the inlet at a constant frequency independent from the IMS dataor ion mobility peak arrival time. The vacuum inlet can also be run in amodulating mode with a constant frequency. In a non-limiting example, ifthe opening pulse is narrower than the IMS peak time (width), the IMS-MScan be operated at a reduced pumping load.

The described IMS system can be used to enable portable MS operation andcan not only be used to control the MS pumping system (reducing thepumping requirement/load), but also used to cleanup the samples by: (1)using a counter current flow can remove all the neutral chemicals from adirty sample; (2) only having ions travel to the IMS-MS interface underguidance of the electric field.

In a situation where rapid switching is required, such as having manyion mobility peaks that need to be sampled in a vacuum, thepiezoelectric valve may not be opened-closed fast enough. Anintelligently placed duration of open-closed timing, can be based on IMSdata outside the vacuum chamber, wherein a wider window may be used tocover several peaks, i.e. open vacuum for a longer period of time.

With a given pumping power, the amount of time for the inlet to open canbe limited, so several approaches can be taken: (1) Open and close at ahigh frequency independent from IMS data or ion mobility peak arrivaltime. The vacuum pump can have a fixed load. The frequency should behigher (the IMS peak width narrower); (2) Open only when ion mobilitypeaks arrive. In FIG. 5, if an IMS spectrum (either a survey scan oron-the-fly IMS spectrum is used to guide the valve) indicates ions onlyarrive from 4.5 to 9.8 ms, then the vacuum window can be open from4.5-9.8 ms for 5.3 ms and closed at the other times. If the totalsampling time is 19.8 ms, the (5.3/19.8)=26.8% time for opening of theinlet could reduce the total pumping power by this factor. Assuming thevacuum pump load is not significant over 5.3 ms period to overload it'spumping capacity. In many cases, the ion mobility (timing) of thetargeted compound is known, then the vacuum inlet only needs to open fora very short period allowing the targeted molecules to enter. In FIG. 5,assuming the targeted compounds have a drift time from 8.6 to 9.8 ms, atiming program can be used to adjust the inlet structure to open 501state at 8.6 ms and to close state at 9.8 ms. The vacuum inlet is openedfor 1.2 ms, i.e. (1.2/19.8)=6% time opening during the operation. (3)The valve is guided by the IMS signal obtained outside the vacuumchamber, or from the MS detector inside the vacuum chamber. When thesurvey scan data is used, a measuring is taken and an IMS spectrum isobtained. Then, depending on the signal intensity and timing location,the vacuum valve could be programmed to open for a period of time whenions arrive. Depending on the control mechanism of the vacuum inlet, thecontrol can be done in real time if the valve can open and close fastenough. In this case, the IMS spectrum obtained outside the vacuumchamber is used to generate a timing diagram of valve open-close timing.Depending on time (t) after detection outside vacuum, the requirement ofvalve operating speed can vary.

An embodiment of the invention is the material and method to control theopening-closing of the valve. This is an electronically actuated dynamicgas aperture. The aperture can be changed in inner diameter by theapplication of an electric current. FIG. 6 shows an aperture 601constructed of a piezoelectric material 602.

The body has metalized electrodes to facilitate the creation of anelectric field that causes the piezoelectric aperture body to expand andtherefore expand the diameter of the aperture. There can be 2, or 4shown in FIG. 7, or a plurality of segmented metalized electrodes. Uponapplication of the electric field the bulk body of the tube expands andthereby the aperture ID 801 increases shown in FIG. 8.

FIG. 9 shows an alternative embodiment of the vacuum inlet 903 that canbe controlled by a mechanical arm that is directed connected a fastmoving driving component. The driving component could be a piece ofpiezoelectric material. A non-limiting configuration of piezoelectriccontrolled vacuum inlet has a mechanical arm 908 that has a surface onone end that can seal against the vacuum inlet body at closed inletposition and is connected the piezoelectric material on the other end.The piezoelectric material controls the movement along the movingdirection 912 to open 910 and close 911 the inlet. The vacuum inletcould be a pinhole, capillary or other narrow opening configurationsthat separates an ambient pressure chamber 901 from a vacuum chamber902. One end of the arm could be polished to form a vacuum seal againstthe inlet body. An alternative configuration is to position the armoutside the vacuum chamber; similar movement could be achieved usingsimilar control mechanism.

FIG. 12 shows an alternative embodiment of a pulsed inlet that can becontrolled by using a deforming, compressing and/or expanding,elastomer. A piezoelectric disk actuator 1205 controls the opening andclosing of the inlet by compressing the elastomer structure (a ring)1204 with the actuator center ring 1202. The elastomer can be madeconductive. The conductive elastomer ring 1204 is set into a retainingdepression in the vacuum inlet flange body 1203. The inlet is shown open1200 and closed 1201.

FIG. 13 shows an alternative embodiment of the pulsed inlet using atorsion seal. A rotating and/or translating disk 1304 rotates ortranslates 1303 to close the conductive elastomer inlet 1305. The inletcan be open 1300, rotationally closed 1301, or translationally closed1302. The conductive elastomer inlet 1305 is set into a retainingdepression in the vacuum inlet flange body 1306.

For configuration of a portable IMS-MS system, the size of vacuumchamber should be maximized, thus the vacuum chamber could beconstructed as the body the instrument. FIG. 10A-B shows a non-limitingexample of the configuration, where the IMS device 1001 is surrounded byvacuum chamber 1002 to achieve maximum size and protection layer of thesensitive instrument. FIG. 10B shows the top view whereby the massanalyzer 1003 is seen. In addition, gas trapping materials with a highsurface area, such as molecular sieves and/or zeolites, can also be usedto absorb gases temporarily in order to maintain the operating vacuumcondition for the mass spectrometer. Such materials could be placed inthe routes of the flow path, pumping lines, and/or adjacent to otherpressure sensitivity components in the vacuum chamber. With the IMS-MSsystem shown in FIG. 10B, a control and data acquisition module locatedon a computer; Signals communicated to the ion mobility separator 1001control the first gate 1004 and second gate 1006 of the ion mobilityseparator, at least a portion of the ions are allowed to enter the ionmobility separator and then allowed to pass through the second gate1006. Drift time (or mobility) of ions are first measured at the iondetector/collector 1007. FIG, 10B shows an aperture 1011 constructed ofa piezoelectric material 1012.

Unless otherwise specified in this document the term “vacuum inlet” isintended to mean an interface with the pressure are different on bothsides, e.g. one said is substantially ambient pressure and the otherside is substantially below ambient pressure; or one side is at areduced pressure, e.g. 10 torrs, and the other side is at even lowerpressure, e.g. millitorrs. In many embodiments illustrated in thisinvent, the vacuum inlet is used while transporting sample (ions) fromrelative high pressure to low pressure, however, the same vacuum inletcan also be used to transport samples from low pressure to highpressure. A non-limiting example would be transporting ions from a massspectrometer to an IMS or flow tube.

Unless otherwise specified in this document the term “ambient pressure”is intended to mean a pressure that is substantially close toatmospheric pressure; the measurement is analysis of the physical and/orchemical properties, which may include analyze samples on the flight orby collecting samples and analyze off-line.

For IMS-MS analysis, ion mobility is preferably measured outside thevacuum chamber (under uniform pressure conditions) for better mobilityresolution and increased accuracy. FIG. 11 schematically illustratesusing measured mobility outside the vacuum chamber to, for example,correct mobility measured inside the vacuum chamber with a MS. Withcommon MS design, additional drift time is added to the mobilitymeasurement when using MS as a detector; ions have traveled through apressure gradient in the IMS-MS interface and low vacuum ion opticswhere additional collision occurs. With the IMS-MS system shown in FIG.11, a control and data acquisition module located on a computer 1115;Signals 1117 communicated to the ion mobility separator 1101 control thefirst gate 1103 and second gate 1105 of the ion mobility separator, atleast a portion of the ions are allowed to enter the ion mobilityseparator and then allowed to pass through the second gate 1105. Drifttime (or mobility) of ions are first measured at the iondetector/collector 1107; the measured ion signal is processed withpreamp 1113 and the data acquisition modules on the computer 1115; aftera portion of the ions travel through the IMS-MS interface, and then aremass separated in MS 1109 and detected on the MS ion detector 1110. Themeasured ion signal is then processed with preamp 1111 and the dataacquisition modules. Ion mobility spectra generated at ion detectors1107 and 1110 are processed by the data acquisition module and mobilitycorrection can be made for each individual ion based on their mobilitymeasured outside the vacuum chamber. In various embodiments, a softwaremodule can be used to realize such correction/calibration. Thisprocedure is preferred when using an ion collector/detector outside thevacuum chamber for sample collection and MS for ion monitoring andidentification. The example of a data acquisition scheme for an IMS-MSsystems shown above can be used for ion collection. Ion Gate 1 and Gate2 are designed to select an ion of interest and to deposit such on thesample collector, or to direct into a mass spectrometer for furtheranalysis or both. Ion mobility spectrometer and mass spectrometer datacan be generated through two separate channels and correlated in thedata acquisition software.

In various embodiments, the ion detector 1107 used to measure ionmobility outside the vacuum chamber, could also be used as an ioncollector that collects at least a portion of the samples for furtheranalysis or other use. In various operational modes of the IMS-MSdevice, selected ions may be allowed to pass the second ion gate 1105.As a large portion of the selected ions are collected on the ioncollector 1107, a small portion of the selected ions may be detected bythe MS to identify their mobilities and mass to charge ratio. Similarly,when an field asymmetric ion mobility spectrometer is used as an ionmobility separator, selected ions are allowed to pass through the IMSand detected either on the ion detection/collection plates or a MSlocated in the vicinity of the detection plates, the rest of the ionsare collected at different location of the full profile ion collectionplate. In various embodiments, the instrument operating parameters, e.g.compensation voltage and RF frequency, may be used to correlate thelocation of ions collected on the full profile ion collection plate andions detected by the MS or ion detection plates.

If the drift time measured outside the vacuum chamber is t_(out) and them/z data is acquired at t_(ms), then the measured m/z data can becorrelated to the mobility data by the factor of a delay time in theinterface for each individual ions.

The method for operating an ion mobility separator and a massspectrometer may include: (a) measuring ion mobility of an analytecomponent using an ion detector/collector at the end of the ion mobilityseparator; (b) measuring ion mobility and mass to charge ratio using anion detector of mass spectrometer; (c) correlating the ion mobility dataobtained from mass spectrometer with the ion mobility data from the ionmobility separator. The ions collected on the ion collector at the endof the IMS are mass identified using the correlated ion mobility data.

The IMS-MS instrument of the present inventions can be operated, invarious embodiments, as a combined preparative or analytical chiralseparation and sample recovery system. For example, with segmented orun-segment Faraday collection plates mounted in the front of MS, amajority of the sample separated by the IMS can be collected on theFaraday plate(s) under high pressure conditions and a small portion ofthe mobility separated sample can be transported through an interface tothe MS. The collection plate can have an opening that matches thegeometry of the IMS-MS interface design. The MS can be used as an onlinemonitoring device for what is collected on the collection plate.Selective collection on this plate can be achieved by using asymmetricIMS as an ion filter, by adding a second ion gate for a symmetric IMS,or both. For example, ions with one mobility property (to the bestresolution of a given device) are collected on a plate, and used forpreparative, analytical purposes, or both. Furthermore, if a transverseelectric field at the interface for MS is used; multiple stage ionmobility based separation can be achieved according to ions symmetric orasymmetric ion mobility properties. In various embodiments, this tandemion mobility separation can produce high mobility separation efficiency.

In various embodiments, a method for operating an instrument comprising:conducting a first measurement using a first instrument; generating atiming program based on the sample arrival time determined by the firstmeasurement; adjusting a vacuum inlet configuration using the timingprogram; and conducting a second measurement using a second instrument.In on embodiment, the first instrument is an ion mobility spectrometerand the second instrument is a mass spectrometer. Alternatively, thefirst and second instrument can be any analytical instruments that arecompatible and can be used as hyphenated instrument. The firstinstrument and the second instrument can be the same. The timing programgenerated using the first measurement can be obtained either on-the-flyor offline during method development time.

In various embodiments, a apparatus of an instrument comprising: a firstinstrument that is used to conduct a first measurement; using the firstmeasurement result that reflects the sample arrival time to generate atiming program; a vacuum inlet is open and/or closed based on the timingprogram, and a second instrument operated under vacuum conditions isused to conduct a second measurement, where the first and secondinstrument can be either ion mobility spectrometer or mass spectrometer.

In various embodiments, a method for operating an instrument comprising:conducting an first measurement using a first method; generating antiming program based on the sample arrival time determined by the firstmeasurement; adjusting operational parameters of a second method usingthe timing program; and conducting an second measurement using thesecond method.

1. A vacuum inlet for a mass spectrometer comprising, a mechanism thatcontrols a vacuum inlet structure for the mass spectrometer a) tomaintain the mass spectrometer at a pressure by dynamically controllingthe size of the vacuum inlet at a first state; and b) to pulse the inletstructure according to a timing diagram to allow some part of a sampleto enter the mass spectrometer, by temporarily changing the inletstructure to a second state; wherein each of the inlet structure statesinvolves opening or closing the vacuum inlet to a particular size. 2.The apparatus in claim 1, further comprises an ion mobility spectrometerthat is outside the vacuum inlet structure.
 3. The apparatus in claim 2,wherein the timing diagram is generated by the ion mobilityspectrometer.
 4. The apparatus of claim 1, wherein the mechanism thatcontrols a vacuum inlet structure includes driving component(s) that areused for maintaining the pressure and/or for pulsing to allow samples toenter the mass spectrometer.
 5. The apparatus of claim 4, wherein thedriving component(s) are selected from: magnetic actuator, piezoelectricactuator, mechanical actuator.
 6. The apparatus of claim 1, whereindynamically controlling the size of the vacuum inlet is performed bydeforming a conductive elastomer.
 7. The apparatus of claim 6, whereinthe conductive elastomer is deformed by compressing, expanding, rotatingand/or translating the conductive elastomer.
 8. The apparatus in claim1, wherein the mechanism involves using a piezoelectric material.
 9. Amethod of operating a vacuum inlet for a mass spectrometer comprising,adjusting a mechanism that controls a vacuum inlet structure for themass spectrometer a) to maintain the mass spectrometer at a pressure bydynamically controlling the size of the vacuum inlet at a first state;and b) to pulse the inlet structure according to a timing diagram toallow some part of a sample to enter the mass spectrometer, bytemporarily changing the inlet structure to a second state; wherein eachof the inlet structure states involves opening or closing the vacuuminlet to a particular size.
 10. The method in claim 9, further comprisesan ion mobility spectrometer that is outside the vacuum inlet structure.11. The method in claim 10, wherein the timing diagram is generated bythe ion mobility spectrometer.
 12. The method in claim 9, whereinadjusting the mechanism that controls a vacuum inlet structure includesoperating driving component(s) that are used for maintaining thepressure and/or for pulsing to allow samples to enter the massspectrometer.
 13. The method in claim 12, wherein the drivingcomponent(s) are selected from: magnetic actuator, piezoelectricactuator, mechanical actuator.
 14. The method in claim 9, whereindynamically controlling the size of the vacuum inlet is performed bydeforming a conductive elastomer.
 15. The method in claim 14, whereinthe conductive elastomer is deformed by compressing, expanding, rotatingand/or translating the conductive elastomer.
 16. The method in claim 9,wherein the mechanism involves using a piezoelectric material.